RIBOZYME MIMICS AS CATALYTIC ANTISENSE REAGENTS

Viral and fungal infections and some cancers may be described as disea ses that are characterized by the expression of certain unwanted prote ins. They could be termed induced genetic disorders, with induction pr ovided by mutation or infection. A comprehensive method to inactivate injurious genes based on their nucleic acid sequences has the potentia l to provide effective antiviral and anticancer agents with greatly re duced side effects. We describe a chemical approach to such gene-speci fic pharmaceutical agents. Our initial efforts have been to develop ne w chemical reagents that can carry out catalytic destruction of specif ic mRNA sequences. We chose hydrolysis as a chemical means of destruct ion, because hydrolysis is compatible with living cells. Our sequence- specific catalytic RNA hydrolysis reagents may be described as functio nal ribozyme mimics. Reactivity is provided by small-molecule catalyst s, such as metal complexes. Specificity is provided by oligonucleotide probes. Here we report initial results on the sequence-specific, hydr olytic cleavage of mRNA from the HIV gag gene, using a ribozyme mimic. The reagent is composed of a terpyridylCu(II) complex for cleavage ac tivity and an oligonucleotide for sequence specificity.